MIT scientists invent technology to replace broken genes or upload new ones

“This is a big breakthrough,” said Maura McGrail, a biologist who uses gene editing to study brain development and disease in animal models at Iowa State University. “It really opens up our ability to edit the genome in ways that can be useful for biomedical research and for gene therapy.”

Such treatments are at least a few years away from being tested in people. So far, the technology has only been tested on human cells grown in a Petri dish and on laboratory mice.

But biotech investors have already lined up to get a stake in the technology and related approaches. Cambridge-based Prime Medicine, Somerville-based Tessera Therapeutics and Watertown-based Tome Biosciences — founded by Abudayyeh and Gootenberg last year — are all working on technologies that aim to add new genes or replace faulty ones to cure disease.

These companies, and others in earlier stages, are developing a third generation of gene-editing technologies based on CRISPR, the revolutionary tool invented just over a decade ago that has allowed biologists to manipulate DNA with ease and precision. Several Boston companies are testing experimental therapies based on previous generations of CRISPR in clinical trials.

The first generation of CRISPR tools relied on a bacterial enzyme called Cas9 to cut DNA at specific sites in the genome, a method that can be used to turn off disease-causing genes. Scientists can also use Cas9 to create an opening to insert a new gene, but this approach is inefficient and prone to introducing unwanted and potentially dangerous mutations.

A second generation of tools, known as base editors, can swap a single letter of the genetic code for another, which can correct typos responsible for inherited diseases. But many diseases are caused by multiple genetic mutations, and creating baseline editing therapies for all of them isn’t realistic.

The third generation of gene editing promises to overcome these limitations with tools and techniques that can tackle a wide variety of diseases more safely and efficiently. Methods have many names. Prime calls it prime editing, Tessera calls it genetic writing, and Tome calls it gene insertion. All of them use complex molecular machines, made of natural enzymes that are modified and stitched together, to add or replace DNA at precise locations in the human genome.

“We now have different technologies to solve a problem that not too long ago had zero solutions,” said Marc Güell, a synthetic biologist at Pompeu Fabra University in Spain who co-founded Integra Therapeutics in Barcelona to develop his own technology. of gene writing. Harvard University geneticist George Church sits on the startup’s science advisory board.

The field is fast becoming one of the most competitive and secretive sectors of the biotech industry. Experts say many of these gene-writing technologies have similarities, but because many companies are shy about the details of their approaches, direct comparisons are hard to make.

Tome, the company founded by Abudayyeh and Gootenberg, is developing “programmable gene insertion,” according to its website, language that mirrors PASTA’s description. But Abudayyeh and Gootenberg declined to confirm Tome is using the technology, and the company did not respond to a request for comment.

The newly published study reveals that a key part of the PASTE technology is an enzyme called integrase, which is used by some viruses to introduce their genes into bacteria. In nature, these enzymes insert viral genes only into specific segments of DNA that function as molecular landing pads. This restriction has made it difficult for scientists to reuse integrases as a tool for inserting genes into human genomes.

Abudayyeh and Gootenberg sought to overcome this problem by combining integrase with two other enzymes that work together to create a landing pad for integrase at the exact spot in the genome where researchers want to insert the therapeutic piece of DNA.

“It’s impressive work, no question about it,” said Erik Sontheimer, a gene-editing researcher and vice president of the RNA Therapeutics Institute at UMass Chan Medical School. New methods of precisely inserting DNA into the genome are “something everyone wants” in the field, he added. Sontheimer is on Tessera’s scientific advisory board.

Two of the three enzymes used in the PASTE technique are the same ones used in the prime editing technique developed by David Liu, a researcher at the Broad Institute of MIT and Harvard, which can be used to add dozens to hundreds of letters of DNA code into a genome.

Some researchers told the Globe that PASTE was essentially a new iteration of prime editing rather than an entirely new technology. Abudayyeh and Gootenberg acknowledged that PASTE relies on prime editing, but stressed that a lot of engineering is needed to get all three enzymes to work together. They also said their approach can be used to add much larger pieces of DNA – up to 36,000 letters long – than raw editing.

Yet the PASTE technique was only 2.5% effective at integrating a new gene into the liver cells of mice. Sontheimer said that means there’s a lot of room for improvement, but noted that other gene-editing technologies also debuted with low success rates that have since improved.

“This is just the first attempt,” he said. “Once you establish your baseline, then you tweak, you tweak, you turn all the knobs you have access to, and those numbers go up.”

Ryan Cross can be reached at Follow him on Twitter @RLCscienceboss.

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